This invention relates to methods and compositions for treating hypertension, endothelial abnormalities or adverse effects induced by administration of sympathetic nervous system antagonists, using endothelin antagonists in combination with sympathetic nervous system antagonists.
The interim analysis of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) has seriously challenged the concept that mean arterial pressure (MAP) lowering per se is an appropriate primary therapeutic endpoint. ALLHAT is an ongoing clinical trial involving more than 40,000 patients with hypertension and at least one other coronary heart disease (CHD) risk factor. It is a randomized, double-blind, active-controlled trial to determine meaningful differences between 4 different antihypertensive agents: a diuretic, chlorthalidone; an xcex11-adrenoceptor antagonist (one type of xe2x80x9calpha-blockerxe2x80x9d), doxazosin; a calcium channel blocker, amlodipine; and an angiotensin converting enzyme (ACE) inhibitor, lisinopril. Recently the published interim report of approximately 24,000 patients by the ALLHAT Data and Safety Monitoring Board (DSMB) recommended discontinuation of one of the treatment arms that involved the xcex11-adrenoceptor antagonist. The conclusions in the interim report stated that the alpha-blocker, when compared with the diuretic, was not effective in preventing cardiovascular end points i.e. it lacked equivalent impact on morbidity and mortality risks (ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group, JAMA 2000;283(15): 1967-1975). Explicitly, the alpha-blocker arm of the study was terminated because patients had an overall 25% increase in the risk of cardiovascular events, including more than twice the risk of congestive heart failure (CHF) within the first two years of the study (ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group, JAMA 2000;283(15): 1967-1975). These serious negative effects occurred despite the fact that the alpha-blocker had beneficial effects both on cholesterol and blood pressure control.
The decision to discontinue the alpha-blocker arm of this trial has widespread implications. In particular the results challenge the conventional assumption that the most important parameter in treatment of hypertension is the lowering of blood pressure. The negative findings from ALLHAT provide compelling evidence that the mechanism of action is a critical consideration in the selection of antihypertensive drugs, i.e., the actions of antihypertensives must be examined beyond their effect on blood pressure. The mechanisms of action of antihypertensive drugs, in general, involve inhibiting processes that are physiological regulators of blood pressure, i.e., blood volume (renin-angiotension system (RAS) inhibitors and diuretics) and vasoconstrictor tone (calcium channel blockers and alpha-adrenoceptor antagonists). Furthermore, it is also recognised that the endothelium is an important contributor in the regulation of the circulation (Cines et a., Blood 1998; 91(10): 3527-3561). It is not surprising, therefore, that endothelial dysfunction has been implicated in the pathogenesis of cardiovascular diseases such as hypertension, atherosclerosis, coronary spastic angina, diabetes and CHF, and further, that endothelial function is now recognized as a therapeutic target for antihypertensive therapies (Ferro and Webb, Drugs 1997; 53 Suppl 1: 30-41). Although certain agents such as ACE inhibitors, and calcium channel blockers are recognised as either protective against, or corrective for, endothelial dysfunction (Naruse et al., J Hypertens 1999; 17(1): 53-60), the relative capacity of different antihypertensive therapies to modify endothelial function has not been fully established. It may be that the beneficial impact of a therapeutic agent on the endothelium is a critical attribute of its clinical efficacy.
Previous findings emphasize the importance of maintaining endothelial function in the regulation of blood pressure, particularly the balance between nitric oxide (NO) and endothelin (ET) (Banting et al., J Hypertens 1996, 14(8): 975-981; Adams et al., Erectile Dysfunction Issues in Current Pharmacology. London: Marin Dunitz, 1998: 11.1-11.12; Adams et al., Int J Impot Res 1996, 8:124; Filep, Hypertension 1997, 30(1 Pt 1): 22-28; Pollock et al., Eur J Pharmacol 1998, 346(1): 43-50; Rees et al., Proc Natl Acad Sci USA 1989, 86(9): 3375-3378; Richard et al., Circulation 1995, 91(3): 771-775). In vivo mechanisms associated with alterations in endothelial function, in particular those linked to these key regulatory factors, have not been elucidated. Previous studies have demonstrated that a deficiency in NO production provokes a marked increase in ET-mediated vasoconstrictor tone, a hallmark of an alteration in vascular function (Banting et al, J Hypertens 1996, 14(8): 975-981; Filep, Hypertension 1997, 30(1 Pt 1): 22-28; Pollock et al., Eur J Pharmacol 1998, 346(1): 43-50; Rees et al., Proc Natl Acad Sci USA 1989, 86(9): 3375-3378; Richard et al., Circulation 1995, 91(3): 771-775).
According to the invention described in detail hereinbelow, we showed that various depressor and antihypertensive agents negatively influence endothelial function as determined by characterizing endothelin-dependent responses. Specifically, in a conscious rat model we assessed the impact of antihypertensive agents, including alpha-adrenoceptor antagonists, ganglionic blockers, and RAS inhibitors, on responses involving endothelial NO-ET balance.
According to a first aspect, the invention provides a method of preventing or inhibiting adverse cardiovascular effects associated with administration of a sympathetic nervous system antagonist in a subject, comprising administering to a subject in need thereof a sympathetic nervous system antagonist and an endothelin antagonist.
The sympathetic nervous system antagonist and the endothelin antagonist may be administered sequentially, or may be coadministered. The sympathetic nervous system antagonist and the endothelin antagonist may be administered as a single dosage unit.
The sympathetic nervous system antagonist may be an alpha-adrenoceptor antagonist. The alpha-adrenoceptor antagonist may be selected from the group consisting of doxazosin, prazosin, terazosin, and phentolamine.
The sympathetic nervous system antagonist may be a ganglionic blocking agent. The sympathetic nervous system antagonist may be selected from the group consisting of hexamethonium, mecamylamine, clonidine, guanethidine, and reserpine.
The endothelin antagonist may be selected from the group consisting of ABT-627, Bosentan, SB209670, and an NO-mimetic.
According to a second aspect, the invention provides a method of treating hypertension in a subject, comprising administering to a subject in need thereof a sympathetic nervous system antagonist and an endothelin antagonist.
The sympathetic nervous system antagonist and the endothelin antagonist may be administered sequentially, or may be coadministered. The sympathetic nervous system antagonist and the endothelin antagonist may be administered as a single dosage unit.
The sympathetic nervous system antagonist may be an alpha-adrenoceptor antagonist. The alpha-adrenoceptor antagonist may be selected from the group consisting of doxazosin, prazosin, terazosin, and phentolamine.
The sympathetic nervous system antagonist may be a ganglionic blocking agent. The sympathetic nervous system antagonist may be selected from the group consisting of hexamethonium, mecamylamine, clonidine, guanethidine, and reserpine.
The endothelin antagonist may be selected from the group consisting of ABT-627, Bosentan, SB209670, and an NO-mimetic.
According to a third aspect, the invention provides a method for improving the efficacy of a sympathetic nervous system antagonist, comprising administering to a subject in need thereof a sympathetic nervous system antagonist together with an endothelin antagonist.
The sympathetic nervous system antagonist and the endothelin antagonist may be administered sequentially, or may be coadministered. The sympathetic nervous system antagonist and the endothelin antagonist may be administered as a single dosage unit.
The sympathetic nervous system antagonist may be an alpha-adrenoceptor antagonist. The alpha-adrenoceptor antagonist may be selected from the group consisting of doxazosin, prazosin, terazosin, and phentolamine.
The sympathetic nervous system antagonist may be a ganglionic blocking agent. The sympathetic nervous system antagonist may be selected from the group consisting of hexamethonium, mecamylamine, clonidine, guanethidine, and reserpine.
The endothelin antagonist may be selected from the group consisting of ABT-627, Bosentan, SB209670, and an NO-mimetic.
According to a fourth aspect of the invention, the invention provides a method of treating prostate cancer or benign prostate hyperplasia (BPH) in a subject, comprising administering to a subject in need thereof a sympathetic nervous system antagonist and an endothelin antagonist.
The sympathetic nervous system antagonist and the endothelin antagonist may be administered sequentially, or may be coadministered. The sympathetic nervous system antagonist and the endothelin antagonist may be administered as a single dosage unit.
The sympathetic nervous system antagonist may be an alpha-adrenoceptor antagonist. The alpha-adrenoceptor antagonist may be selected from the group consisting of doxazosin, prazosin, terazosin, and phentolamine.
The sympathetic nervous system antagonist may be a ganglionic blocking agent. The sympathetic nervous system antagonist may be selected from the group consisting of hexamethonium, mecamylamine, clonidine, guanethidine, and reserpine.
The endothelin antagonist may be selected from the group consisting of ABT-627, Bosentan, SB209670, and an NO-mimetic.